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• W2065156973 abstract "“Restenosis” is the term which has been used to denote recurrent narrowing of a blood vessel after an initially successful revascularization procedure, such as percutaneous transluminal angioplasty (PTA). Despite the fact that PTA has now been used widely to treat atherosclerotic obstructions in the coronary and peripheral vascular circulations for nearly three decades, restenosis continues to be a vexing, and consequently expensive, complication of this otherwise efficacious intervention. In certain regions of the circulatory system, the incidence of restenosis has been so high that it has seriously limited enthusiasm for the application of PTA. The superficial femoral artery (SFA)/popliteal artery of the leg constitutes one such site. While the acute procedural success for percutaneous revascularization of lesions in the SFA using conventional guidewires and standard PTA is well in excess of 90%, published reports have established that restenosis may complicate the clinical course of as many as 60% of patients undergoing PTA for obstruction of the SFA. Given that disease of the SFA represents one of the most frequent sites of peripheral vascular obstruction, the disappointing durability of PTA for SFA lesions has serious implications. While bypass surgery may be often used to successfully treat these patients, such surgery is not risk-free, particularly in a population of patients with a high frequency of co-morbid diseases, including coronary and carotid disease. The cost, recuperation time, and frequent requirement for a patient's native veins (the supply of which is fixed and the need for which may extend to coronary bypass or repeat lower extremity bypass surgery) as conduits constitute additional liabilities of SFA bypass surgery. Previous strategies to limit the development of restenosis by non-mechanical means have employed antiproliferative, antiplatelet, anti-coagulant, anti-inflammatory, spasmolytic, and lipid-lowering therapies; none have proved to be effective. Curiously, despite: a) the fact that PTA routinely produces extensive endothelial denudation, and b) the accepted roles of the endothelium in providing barrier function, reducing thrombogenicity, and inhibiting restenosis, treatment strategies designed specifically to restore endothelial integrity have not been previously explored for restenosis prevention. In an attempt to improve upon the results of SFA/popliteal PTA, we have therefore considered that acceleration of re-endothelialization may be achieved following administration of mitogens which promote endothelial cell migration and/or proliferation. These include vascular endothelial growth factor (VEGF). The rationale and experimental findings for administration of recombinant protein and/or the gene encoding VEGF in 2 different animal models are outlined in the accompanying manuscripts attached to this proposal. Briefly, these studies demonstrate that VEGF accelerates re-endothelialization and thereby reduces intimal thickening. Accordingly, the purpose of this clinical protocol is to document the safety of interventional re-endothelialization achieved in this case by percutaneous catheter-based delivery of the gene encoding vascular endothelial growth factor (VEGF) in patients with claudication due to SFA obstruction. A secondary objective is to investigate the bioactivity of this strategy for inhibiting restenosis. Plasmid DNA encoding for the 165-amino acid isoform of VEGF will be delivered post-PTA using a hydrogel-polymer coated balloon angioplasty catheter, in the absence of associated viral or other vectors. Patients will be studied pre- and post-PTA by a variety of non-invasive and invasive tests for evidence of safety as well as bioactivity. This preliminary study may yield evidence that gene therapy designed to accelerate re-endothelialization at the site of PTA-induced endothelial disruption may represent a novel strategy for inhibition of restenosis in peripheral as well as coronary artery disease. “Restenosis” is the term which has been used to denote recurrent narrowing of a blood vessel after an initially successful revascularization procedure, such as percutaneous transluminal angioplasty (PTA). PTA involves the use of a tiny balloon mounted on a catheter that can be advanced under x-ray guidance to the site of a blocked artery. When the balloon is inflated, the blockage—and corresponding obstruction to blood flow—is thereby reduced. Despite the fact that PTA has now been used widely to treat atherosclerotic blockages in the coronary and peripheral blood vessels for nearly three decades, restenosis continues to be a vexing, and consequently expensive, complication of this otherwise effective intervention. In certain regions of the circulatory system, the incidence of restenosis has been so high that it has seriously limited enthusiasm for the application of PTA. The superficial femoral artery (SFA)/popliteal artery of the leg constitutes one such site. Published reports have established that restenosis may complicate the clinical course of as many as 60% of patients undergoing PTA for obstruction of the SFA. Because disease of the SFA represents one of the most frequent sites of arterial blockage in the leg, the high incidence of restenosis following PTA of this artery implies that patients in whom blockage of the SFA is causing leg pain upon walking (“claudication”) must seek alternative treatment. While bypass surgery may be often used to successfully treat these patients, such surgery is not risk-free, particularly when such patients typically suffer from blockages in the arteries supplying blood flow to the heart (coronary arteries) and/or head (carotid arteries). The cost, recuperation time, and frequent requirement for a patient's native veins (the supply of which is fixed and the need for which may extend to coronary bypass or repeat leg bypass surgery) as bypass conduits constitute additional liabilities of SFA bypass surgery. The inner lining of the blood vessels is composed of cells called “endothelial” cells. These cells have important protective functions. Specifically, these cells make certain proteins that appear to be important in preventing the formation of blood clots or artherosclerotic plaques that may block blood flow through the arteries. Unfortunately, when a PTA catheter is used to “crush” a blockage in an artery, it also typically destroys the endothelial cell lining at that site. Animal experiments suggest that the relatively long time which may be required for these endothelial cells to grow back over the PTA site may be one of the principal factors responsible for restenosis. Accordingly, the purpose of this clinical protocol is to document the safety of re-endothelialization, achieved in this case by percutaneous catheter-based delivery of the gene encoding vascular endothelial growth factor (VEGF) in patients with claudication due to SFA obstruction. A second objective is to investigate the bioactivity of this strategy for inhibiting restenosis. Patients will be studied pre- and post-PTA by a variety of non-invasive and invasive tests for evidence of safety as well as bioactivity. This preliminary study may yield evidence that gene therapy designed to accelerate re-endothelialization at the site of PTA-induced endothelial disruption may represent a novel strategy for inhibition of restenosis in peripheral as well as coronary artery disease." @default.
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• W2065156973 date "1996-05-20" @default.
• W2065156973 modified "2023-09-25" @default.
• W2065156973 title "Arterial Gene Therapy for Restenosis. St. Elizabeth's Medical Center, Tufts University School of Medicine, Boston, Massachusetts" @default.
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• W2065156973 doi "https://doi.org/10.1089/hum.1996.7.8-989" @default.
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